Myogenic Stem Cell Function in Aging Skeletal Muscle

描述（由申请人提供）：本申请旨在破译支持卫星细胞功能的分子途径，并了解这些途径在衰老过程中如何受到影响。骨骼肌相关的骨骼肌退化（少肌症）的特征在于质量、力量、耐力和修复能力的下降，以及肌纤维之间和肌纤维内的脂肪积累。肌纤维修复是由卫星细胞，肌源性干细胞位于肌纤维基板。在日常肌肉活动中发生的细微肌肉损伤在整个生命中不断提高对功能性肌纤维修复的需求。然而，卫星细胞性能在老年时下降，这种下降可能是肌肉减少症的一个促成因素。虽然卫星细胞一直被认为是典型的组织特异性肌祖细胞的功能，我们已经表明，他们也可以进入间充质替代路径，最终在终末成脂分化。这种替代性的谱系定型可能导致老年时肌原性受损和肌肉肥胖增加。深入了解参与损害卫星细胞自我更新和肌性的机制，并促进其间充质可塑性，将有助于设计治疗方法，以改善衰老肌肉中肌源性祖细胞的数量和功能。因此，本提案的目的是：1）研究卫星细胞贡献肌源性后代并在整个生命中进行自我更新的潜力。2)确定肌源性转录因子Myf5和MyoD以及肌肉整合素α 7在卫星细胞的肌源性与间充质替代命运之间的平衡中的作用。3)探讨金属蛋白酶和去整合素活性对间充质命运和卫星细胞自我更新的影响。将研究从幼年至老年年龄组的野生型和转基因小鼠。卫星细胞的性能将在分离的肌纤维和克隆，使用蛋白质和RNA表达方法进行检查。此外，相关基因的功能作用将通过用基于病毒的表达载体转导卫星细胞来确定。拟议的研究将为成人和衰老肌肉中卫星细胞的状态提供新的见解，因此，将为疾病和衰老期间的肌肉康复策略提供重要信息。 骨骼肌修复是由称为卫星细胞的肌原祖细胞实现的。这些细胞的性能下降可能是老年骨骼肌退化（肌肉减少症）的一个促成因素。拟议的研究将为整个生命周期中卫星细胞功能的调节提供新的见解，因此，将为疾病和衰老期间的肌肉康复策略提供重要信息。

DESCRIPTION (provided by applicant): This application aims at deciphering the molecular pathways supporting satellite cell function and at understanding how these are influenced during aging. Age-related skeletal muscle deterioration (sarcopenia) is characterized by a decline in mass, strength, endurance and repair capacity, and by fat accumulation between and within myofibers. Myofiber repair is enabled by satellite cells, myogenic stem cells situated underneath the myofiber basal lamina. Subtle muscle injuries that occur during routine muscle activity raise a continuous demand for functional myofiber repair throughout life. However, satellite cell performance declines in old age and this decline can be a contributory factor to sarcopenia. While satellite cells have classically been thought to function as tissue-specific myogenic progenitors, we have shown that they can also enter a mesenchymal alternative path, which culminates in terminal adipogenic differentiation. Such an alternative lineage commitment may contribute to impaired myogeneity and increased muscle adipostiy in old age. Gaining insight into mechanisms involved in impairing satellite cell self-renewal and myogeneity, and in promoting their mesenchymal plasticity, will contribute to the design of therapies to improve the number and function of myogenic progenitors in aging muscle. Accordingly, the aims of this proposal are: 1) Investigate the potential of satellite cells to contribute myogenic progeny and undergo self-renewal throughout life. 2) Determine the role of the myogenic transcription factors Myf5 and MyoD, and the muscle integrin alpha7, in the balance between myogenic versus mesenchymal alternative fate of satellite cells. 3) Investigate the effect of metalloproteinase and disintegrin activities on mesenchymal fate and self-renewal of satellite cells. Wildtype and genetically modified mice, of age groups ranging from juvenile to senile, will be investigated. Satellite cell performance will be examined in isolated myofibers and clones, using protein and RNA expression methodologies. Additionally, the functional role of relevant genes will be determined by transducing satellite cells with viral-based expression vectors. The proposed studies will contribute new insight into the status of satellite cells in adult and aging muscles, and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging. Skeletal muscle repair is enabled by myogenic progenitors named satellite cells. Age-associated decline in the performance of these cells can be a contributory factor to the deterioration of skeletal muscle in old age (sarcopenia). The proposed studies will contribute new insight into the regulation of satellite cell function throughout the lifespan and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging.